The p53 protein is a stress-responsive transcription factor which is induced by a variety of stimuli that act through mechanisms that alter p53 half-life (Ko and Prives, 1997; Levine, 1997). It is encoded by a tumour suppressor gene that is frequently mutated in human cancer cells (Greenblat, 1994). In normal cells p53 exerts its function through the targeted sequence-specific activation of a number of different p53-responsive genes. These genes include waf1, bax, mdm2 and gadd45 which encode proteins that give rise to the physiological consequences of p53 activation, namely apoptosis or cell cycle arrest (Ko and Prives, 1997). p53 alleles isolated from tumour cells frequently harbour mutations that disrupt p53 DNA binding activity (Cho et al., 1994), underscoring the importance of transcription-related functions in mediating the effects of p53 tumour suppression.
The pathways through which p53 activity is regulated have been subject to intense study. The transcriptional activation domain of p53 is targeted by the MDM2 oncoprotein, which thereafter prevents p53 from activating transcription by hindering the interaction of p53 with the transcription apparatus (Oliner et al., 1993; Lin et al., 1994). In this respect, MDM2 can override the physiological effects of p53 response (Wu et al., 1993), and it is consistent with this idea that mdm2 is often seen to be aberrantly expressed in human tumour cells (Piette et al., 1997). A further consequence of the interaction between MDM2 and p53 is a down-regulation in the level of p53 protein, which is mediated in part through a ubiquitin-dependent pathway and requires the MDM2 E3 ligase (Haupt et al., 1997; Honda et al., 1997; Kubbutat et al., 1997).
Because p53 inactivation is associated with many human cancers, research has been directed at restoring p53 function, in order to provide a therapy for these cancers. p53 may also make normal cells sensitive to stress and recently, research has also been directed at the temporary inhibition of p53 (Komarova E. and Gudkov A. (1998) Seminars in Cancer Biology 8(5) 389-400). This inhibition may be useful in ameliorating the p53 induced side effects of cancer therapies such as radio-and chemo-therapy, which include hair loss and damage to the lymphoid and haematopoietic systems and the intestinal epithelia.
Adverse effects associated with the activation of P53 have also been described in other conditions including injury associated cellular stress (e.g. burns), diseases associated with fever, local hypoxia conditions associated with a deficient blood supply (e.g. stroke and ischaemia) and cell aging (e.g. fibroblast senescence). Suppression of p53 activity may therefore be useful in therapies related to these conditions.
A considerable body of evidence supports a role for the p300/CBP family of co-activators in p53-dependent transcription (Shikama et al., 1997). For example, p300/CBP proteins physically interact with the p53 activation domain, and dominant-negative derivatives of p300/CBP proteins can block p53 activity (Avantaggiati et al., 1997; Gu et al., 1997; Lill et al., 1997; Lee et al., 1998). Moreover, phosphorylation of the p53 activation domain during the stress response is believed to antagonise the interaction with MDM2, and possibly stabilise the interaction with p300/CBP proteins (Sheih et al., 1997; Giaccia and Kastan, 1998; Chehab et al., 2000; Shieh et al., 2000). However, p300/CBP proteins function as integral components of larger multicomponent co-activator complexes, and a variety of co-factors that make up p300/CBP complexes have been identified (Shikama et al., 1997; Shiltz and Nakatani, 2000). Of considerable interest is the JMY co-factor, which is an integral component of the p300 co-activator complex that augments the transcriptional activity of p53, and enhances the level of the p53 response (Shikama et al., 1999). No other components of the p300 complex transcription have been characterised which are involved in regulating p53.